Pharmaceutical composition and the process for its preparation

ABSTRACT

The present invention provides a new stable pharmaceutical composition containing 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione as active ingredient.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. 119 of U.S.provisional application No. 60/207,888 filed May 30, 2000 and claimspriority under 35 U.S.C. 120 of U.S. patent application Ser. No.09/578,887 filed May 26, 2000 and U.S. patent application Ser. No.09/863,986 filed May 23, 2001 and International Patent ApplicationPCT/DK00/00291 filed May 30, 2000, the contents of which are fullyincorporated herein by reference.

BACKGROUND

[0002] The subject-matter of the present invention is a newpharmaceutical composition containing5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dioneas active ingredient and the process for its preparation.

[0003]5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dioneand pharmaceutically acceptable salts thereof have been found useful inthe treatment of type 2 diabetes acting as a insulin sensitizer asdisclosed in PCT Publication WO 97/41097.

[0004] The active ingredient is present as the base or as apharmaceutically acceptable salt, preferably as the potassium salt.

[0005] Various solutions have been proposed for the preparation ofmedications based on5[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione.

BRIEF DESCRIPTION OF THE INVENTION

[0006] The aim of the present invention is to provide a new compositionintended for the preparation of5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dionewith improved stability, in particular solid dosage forms thereof.

[0007] It has been found in fact that5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]-phenylmethyl]thiazolidine-2,4-dioneand its pharmaceutically acceptable salts may decompose in the presenceof and in contact with water. Further it has been observed thatdecomposing may occur in the presence of oxygen.

[0008] Thus, from a first aspect, the subject-matter of the presentinvention is a pharmaceutical composition intended for the preparationof dosage forms and in particular solid dosage forms containing anefficacious quantity of5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dioneor of one of its pharmaceutically acceptable salts as active ingredient.

[0009] The present invention is based on the surprising discovery of thefact that the stability of5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione,or of one of its pharmaceutically acceptable salts, can be considerablyimproved in preparations containing5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dioneor of its pharmaceutically acceptable salts and antioxidant agent if theproduct is composed of excipients which do not contain water.

[0010] In another embodiment of the present invention, thepharmaceutical composition does not contain an antioxidant agent.

DETAILED DESCRIPTION

[0011] Pharmaceutically acceptable salts forming part of this inventioninclude salts such as alkali metal salts like Li, Na, and K salts,alkaline earth metal salts like Ca and Mg salts, salts of organic basessuch as lysine, arginine, guanidine, diethanolamine, choline and thelike, ammonium or substituted ammonium salts, aluminium salts. Salts mayinclude acid addition salts where appropriate which are, sulphates,nitrates, phosphates, perchlorates, borates, hydrohalides, acetates,tartrates, maleates, citrates, succinates, palmoates,methanesulphonates, benzoates, salicylates, hydroxynaphthoates,benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and thelike.

[0012]5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione,together with a conventional adjuvant, antioxidant carrier, or diluent,and if desired a pharmaceutically acceptable acid addition salt thereof,may be placed into the form of pharmaceutical compositions and unitdosages thereof, and in such form may be employed as solids, such astablets or filled capsules, or oral powders to be diluted immediatelybefore use filled with the same, all for oral use, in the form ofsuppositories for rectal administration; or as pessaries for vaginaluse; or in the form of sterile injectable powders for parenteral,transdermal, nasal, pulmonary and ocular use.

[0013] Within the framework of the present description and of theclaims, by powders is meant any mixture of components, granulated ornot, intended to be placed in solution and/or in suspension in water, oragain to be ingested directly or by any other appropriate means as forexample in a mixture with a food product.

[0014] In accordance with a particular characteristic of the invention,the manufacture of tablets is carried out as a direct compression.

[0015] In accordance with another particular characteristic, thiscomposition also contains pharmaceutically acceptable excipients.

[0016] In accordance with a particular characteristic of the invention,the antioxidant agent cited above is selected from among α-tocopherol,γ-tocopherol, δ-tocopherol, extracts of natural origin rich intocopherol, L-ascorbic acid and its sodium or calcium salts, ascorbylpalmitate, propyl gallate (PG), octyl gallate, dodecyl gallate,butylated hydroxy anisole (BHA) and butylated hydroxy toluene (BHT).

[0017] In accordance with a currently preferred embodiment, theantioxidant agent will be α-tocopherol.

[0018] In accordance with another particular characteristic of theinvention, the diluent is lactose and/or cellulose microcrystalline,magnesium stearate, talc. However, any other pharmaceutically acceptablediluents could be used if the diluents have low water content. Thequantities of diluents can be easily determined by a person skilled inthe art and depend of course on the final pharmaceutical form required.

[0019] Generally speaking, a composition which complies with the presentinvention and which are intended for the preparation of tablets, maycontain, expressed in parts by weight per 100 parts of5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione,or of one of its pharmaceutically acceptable salts:

[0020] between 100 and 400,000 parts by weight of anhydrous lactose;

[0021] between 1 and 100 parts by weight of an antioxidant;

[0022] between 50 and 500 parts by weight of pregelatinized starch;

[0023] between 1000 and 10,000 parts by weight of microcrystallinecellulose;

[0024] between 10 and 500 parts by weight of crospovidone;

[0025] between 10 and 500 parts by weight of silicon dioxide;

[0026] between 10 and 500 parts by weight of hydrogenated vegetable oil;

[0027] between 10 and 500 parts by weight of magnesium stearate;

[0028] between 10 and 500 parts by weight of hydroxypropylmethylcellulose;

[0029] between 10 and 500 parts by weight of hydroxypropyl cellulose;

[0030] between 1000 and 10,000 parts by weight of mannitol;

[0031] between 10 and 500 parts by weight of stearic acid; or

[0032] between 10 and 500 parts by weight of titanium dioxide.

[0033] According to a preferred embodiment of the invention the watercontent of the excipients is very low. More specifically the watercontent in the diluents is very low in order to minimize the watercontent of the pharmaceutical composition. Lactose is used in itsanhydrous form. Furthermore, all excipients may be applied in a dryform.

[0034] A convenient way of preparing the composition according to thepresent invention is only to use starting materials (excipients) havinga low content of water. Preferably all starting materials used for thepreparation of the composition according to the present invention shouldhave a water content below about 1%, preferably below about 0.5%, morepreferred below about 0.1%, and even more preferred below about 0.05%,(weight/weight).

[0035] Preferably, the composition according to the present inventionshould have a water content below about 1%, preferably below about 0.5%,more preferred below about 0.1%, (weight/weight).

[0036] In accordance with a second aspect, the subject-matter of thepresent invention is a pharmaceutical preparation, in the form of tabletor powder, characterised in that it contains a composition as definedpreviously associated if required with at least one customary additiveselected from among the sweeteners, flavouring agents, colours andlubricants. A person skilled in the art can easily determine the choiceof these additives and their quantity.

[0037] Another manufacturing process for pharmaceutical compositionsaccording to the invention is mixing of5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione,one or more antioxidants and other pharmaceutical excipients followed bymelt granulation in a high shear mixer. Hydrogenated, vegetable oil,waxes or other low temperature melting binders can be used. The granulescan be filled into capsules, compressed into tablets or used in otherpharmaceutical dosage forms.

[0038] More preferably the manufacturing process applied is directcompression of tablets, wherein5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine2,4-dione,one or more antioxidants and other excipients suitable for directcompression are mixed followed by tabletting.

[0039] Yet, another preferred embodiment of the manufacturing process iswet granulation, where granules are obtained by wet massing of5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione,together with one or more antioxidants and other excipients.

[0040] It is assumed that the contact time with water has to be veryshort.

[0041] The most preferred process comprises the direct compressionwhereby5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dioneis kept at conditions of low water vapour pressure.

[0042] A sweetener may be a natural sugar such as sorbitol or asynthetic product such as saccharine or aspartame.

[0043] When the antioxidant selected is ascorbylpalmitat, propylgallat,which is a powder, it can be advantageous to mix it in an appropriateexcipient such as α-tocopherol succinat, lactose or cellulosemicrycrystalline.

[0044]5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dionehas the formula:

[0045] The present invention will further be illustrated with thefollowing non-exhaustive examples.

EXAMPLES

[0046] In Example 1 through 4 the tablets were prepared according to thefollowing procedure:

[0047] The active ingredient is mixed with cellulose microcrystalline ina drum mixer for 10 minutes. Lactose is added and the mixing continuedfor further two minutes. The lubricants are added and the mixingcontinued for further two minutes.

EXAMPLE 1

[0048] 25 mg5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione,Potassium Salt Tablets 807227 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-   9%quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4- dione, potassiumsalt, 003/97 Cellulose Microcrystallline  20% Lactose  66% MagnesiumStearate 0.5% Talc 4.5%

EXAMPLE 2

[0049] 50 mg5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione,Potassium Salt Tablets 807237 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-  18%quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4- dione, potassiumsalt, 003/97 Cellulose Microcrystalline  20% Mannitol  57% MagnesiumStearate 0.5% Talc 4.5%

EXAMPLE 3

[0050] 50 mg5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione,Potassium Salt Tablets 731725 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-   18%quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4- dione, potassiumsalt Lactose 81.5% Magnesium stearate  0.5%

EXAMPLE 4

[0051] 0.25 mg5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione,Potassium Salt Tablets 728625 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2- 0.09%quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4- dione, potassiumsalt Mannitol   98% Magnesium stearate   2%

EXAMPLE 5

[0052] 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2- 0.09%quinazolinyl]methoxy]phenylmethyl]thiazolidine- 2,4-dione, potassiumsalt Hydrogenated vegetable oil 6.25% Talc   5% α-tocopherol   50% of5-[[4-[3- methyl-4-oxo-3,4- dihydro-2- quinazolinyl]methoxy]phenylmethyl] thiazolidine-2,4- dione, potassium salt LactoseDCL21/Mannitol Up to 200 g

[0053] The granulate is manufactured in a Baker Perkins 1 L high-shearmixer—using a water bath of 70° C. The mixing is carried out at 3000RPM, chopper 6000 RPM and the granulation is performed at approx. 70° C.The hot granulate is sieved through sieve 1.25 μm, and the coldgranulate through sieve 1000 μm. The glidant is added with a card for 2min. The tablets are manufactured using a Diaf tablet machine with 9 mmpunch. In order to protect against light and improve the appearance ofthe tablets, the tablets are film-coated.

[0054] The tablets were coated with the following film-coatingcomposition where an amount of coating material of 5 mg/cm² were chosenas being satisfactory with respect to stability of the tablets:Methylhydroxypropylcellulose, Ph. Eur. ˜4.34 mg/tablet Titanium Dioxide,Ph. Eur. ˜1.73 - Purified Water, Ph. Eur. q.s. -

EXAMPLE 6

[0055] 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2- 0.09%quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4- dione, potassiumsalt Povidone  7.5% Hydroxypropylmethyl cellulose  1.5% Croscarmelosesodium 1.56% Talc  1.1% Magnesium stearate  0.5% Lactose 300 mesh up to200 g

[0056] The granulate is manufactured by Baker Perkins 1 L intensivemixer. Dry mixing were carried out at 500 RPM, chopper 1500 RPM andgranulation 1000 RPM and 2000 RPM. The wet granulate is sieved throughsieve 1.25 μm and the dry granulate through sieve 1000 μm. The glidantis admixed with a card for 2 min. The tablets are manufactured by Diaftablet machine with 9 mm punch.

EXAMPLE 7

[0057] Composition: Oral Powder,    1 mg/ml,   100 ml5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2- 0.1096 gquinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4- dione potassium saltMannitol   2.5 g Hydroxypropyl-β-cyclodextrin    10 g

EXAMPLE 8

[0058] Composition: Oral Powder,   10 mg/ml,   100 ml5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2- 1.096 gquinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4- dione potassium saltMannitol  2.5 g Hydroxypropyl-β-cyclodextrin   10 g Sodium Carbonate,anhydrous,   15 mg Na₂CO₃

1. A pharmaceutical composition comprising (i) a compound selected fromthe group consisting of5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dioneand a pharmaceutically acceptable salt thereof, and (ii) one or more ofa a pharmaceutically acceptable carrier or excipient, wherein saidmixture has a water content below about 1%(w/w).
 2. The composition ofclaim 1 in the form of a tablet, a powder or a capsule.
 3. Thecomposition of claim 1, further comprising an antioxidant.
 4. Thecomposition of claim 3, wherein said antioxidant comprises between 1 and100 parts by weight and the pharmaceutically acceptable excipient isselected from the group consisting of: between 100 and 400,000 parts byweight of anhydrous lactose, between 1 and 100 parts by weight of anantioxidant, between 50 and 500 parts by weight of pregelatinizedstarch, between 1000 and 10,000 parts by weight of microcrystallinecellulose, between 10 and 500 parts by weight of crospovidone, between10 and 500 parts by weight of silicon dioxide, between 10 and 500 partsby weight of hydrogenated vegetable oil, between 10 and 500 parts byweight of magnesium stearate, between 10 and 500 parts by weight ofhydroxypropyl methylcellulose, between 10 and 500 parts by weight ofhydroxypropyl cellulose, between 1000 and 10,000 parts by weight ofmannitol, between 10 and 500 parts by weight of stearic acid, or between10 and 500 parts by weight of titanium dioxide.
 5. The pharmaceuticalcomposition of claim 1, wherein the water content is below about 0.5%(w/w).
 6. The pharmaceutical composition of claim 5, wherein the watercontent is below about 0.1% (w/w).
 7. The pharmaceutical composition ofclaim 6, wherein water content is below about 0.05% (w/w).
 8. Thecomposition of claim 3, wherein the antioxidant is selected from groupconsisting of: α-tocopherol, γ-tocopherol, δ-tocopherol, extracts ofnatural origin rich in tocopherol, L-ascorbic acid and its sodium orcalcium salts, ascorbyl palmitate, propyl gallate (PG), octyl gallate,dodecyl gallate, butylated hydroxy anisole (BHA), and butylated hydroxytoluene (BHT).
 9. The composition of claim 8, wherein the antioxidant isα-tocopherol.
 10. The pharmaceutical composition of claim 1, furthercomprising at least one customary additive selected from the groupconsisting of sweeteners, flavouring agents, colours and lubricants. 11.The composition of claim 1 comprising (i) a compound selected from thegroup consisting of5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiadiazolidine-2,4-dioneand a pharmaceutically acceptable salt thereof, and (ii)pharmaceutically acceptable excipients comprising anhydrous lactose,microcrystalline cellulose, magnesium stearate, and talc.
 12. Thecomposition of claim 11, wherein the pharmaceutically acceptableexcipients are: between 100 and 400,000 parts by weight of anhydrouslactose, between 1000 and 10,000 parts by weight of microcrystallinecellulose, and between 10 and 500 parts by weight of magnesium stearate,expressed in parts by weight per 100 parts of5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiadiazolidine-2,4-dione,or of one of its pharmaceutically acceptable salts.
 13. The compositionof claim 12, wherein the amount of talc is 0-10% (weight/weight). 14.The composition of claim 1, comprising:5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-   9%quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4- dione, potassiumsalt cellulose microcrystallline  20% lactose  66% magnesium Stearate0.5% talc 4.5%


15. The composition of claim 1, comprising: dione, potassium salt 18%cellulose microcrystalline 20% mannitol 57% magnesium stearate 0.5% talc 4.5% 


16. The composition of claim 1, comprising: dione, potassium salt   18%lactose 81.5% magnesium stearate  0.5%


17. The composition of claim 1, comprising: dione, potassium salt 0.09%mannitol   98% magnesium stearate   2%


18. The composition of claim 1, comprising: dione, potassium salt 0.09%hydrogenated vegetable oil 6.25% talc   5% α-tocopherol   50% of5-[[4-[3-methyl-4-oxo-3,4-dihydro- 2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione, potassium salt lactose DCL21/mannitol Up to 200g.


19. The composition of claim 1, comprising: dione, potassium salt 0.09%povidone  7.5% hydroxypropylmethyl cellulose  1.5% croscarmelose sodium1.56% talc  1.1% magnesium stearate  0.5% lactose 300 mesh up to 200 g.


20. The composition of claim 1, comprising the following: dione,potassium salt 0.1096 g mannitol 2.5 g hydroxypropyl-β-cyclodextrin 10 gand diluted with 92 mL water before use.


21. The composition of claim 1, comprising: dione, potassium salt 1.096g mannitol 2.5 g hydroxypropyl-β-cyclodextrin 10 g sodium carbonate,anhydrous, 15 mg Na₂CO₃ and diluted with 92 mL water before use.